Mayfield was also involved in several business ventures including the wholesale grocery industry and operation of several farms.

In 1922, Mayfield was one of six candidates who challenged five-term United States Senator Charles A. Culberson for the Democratic senatorial nomination.

In the ensuing runoff between Mayfield and former Governor James E. Ferguson, Mayfield was openly allied with the Ku Klux Klan[3][6] in support of prohibition and continued segregation of Whites and Blacks, while Ferguson spoke-out against the Klan and was strongly against prohibition.

Senator from Texas, Morris Sheppard of Texarkana, Mayfield won the Democratic nomination.

In the general election held on November 7, 1922, Mayfield faced the Independent candidate George Peddy, who also had the backing of the Republican Party.

After the election, Peddy challenged the results on the grounds of disputes over filing deadlines and other technical issues.

Mayfield received the honorary degree of doctor of humane letters from John Brown University in Siloam Springs, Arkansas.